1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE AND PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE COMPOUNDS FOR USE AS ADENOSINE A2a RECEPTOR ANTAGONISTS

ABSTRACT

Compounds of the Formula I wherein R 1  and R 2  together with the carbon atoms to which they are bonded optionally form a further heteroaromatic ring of the formula (II) as well as pharmaceutically acceptable salts, solvates, esters and prodrugs thereof are adenosine A2a receptor antagonists and, therefore, are useful in the treatment of central nervous system diseases, in particular Parkinson&#39;s disease.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 1,2,4-triazolo[4,3-c]pyrimidin-3-oneand pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidine-3-one adenosineA_(2a) receptor antagonist compounds, methods of using said compounds inthe treatment of central nervous system diseases, in particularParkinson's disease, and to pharmaceutical compositions comprising saidcompounds.

2. Description of Related Art

Adenosine is known to be an endogenous modulator of a number ofphysiological functions. At the cardiovascular system level, adenosineis a strong vasodilator and a cardiac depressor. On the central nervoussystem, adenosine induces sedative, anxiolytic and antiepilepticeffects. On the respiratory system, adenosine inducesbronchoconstriction. At the kidney level, it exerts a biphasic action,inducing vasoconstriction at low concentrations and vasodilation at highdoses. Adenosine acts as a lipolysis inhibitor on fat cells and as anantiaggregant on platelets.

Adenosine action is mediated by the interaction with different membranespecific receptors which belong to the family of receptors coupled withG proteins. Biochemical and pharmacological studies, together withadvances in molecular biology, have allowed the identification of atleast four subtypes of adenosine receptors: A₁, A_(2a), A_(2b) and A₃.A₁ and A₃ are high-affinity, inhibiting the activity of the enzymeadenylate cyclase, and A_(2a) and A_(2b) are low-affinity, stimulatingthe activity of the same enzyme. Analogs of adenosine able to interactas antagonists with the A₁, A_(2a), A_(2b) and A₃ receptors have alsobeen identified.

Selective antagonists for the A_(2a) receptor are of pharmacologicalinterest because of their reduced level of side effects. In the centralnervous system, A_(2a) antagonists can have antidepressant propertiesand stimulate cognitive functions. Moreover, data has shown that A_(2a)receptors are present in high density in the basal ganglia, known to beimportant in the control of movement. Hence, A_(2a) antagonists canimprove motor impairment due to neurodegenerative diseases such asParkinson's disease, senile dementia as in Alzheimer's disease, andpsychoses of organic origin.

Some xanthine-related compounds have been found to be A₁ receptorselective antagonists, and xanthine and non-xanthine compounds have beenfound to have high A_(2a) affinity with varying degrees of A_(2a) vs. A₁selectivity.

Triazolo-pyrimidine adenosine A_(2a) receptor antagonists have beendisclosed previously, for example in WO 95/01356; U.S. Pat. No.5,565,460; WO 97/05138; WO 98/52568; WO 01/92264; PCT/US02/32630; filedOct. 11, 2002; U.S. Pat. No. 6,897,217; US 20050239795A1; US20070066620A1; WO05/103055; WO07/035,542A1; Bioorg. Med. Chem. Lett.,15: 3670-3674 (2005); and Bioorg. Med. Chem. Lett., 15: 3675-3678(2005).

Adenosine A_(2a) receptor antagonists have been disclosed as beinguseful in the treatment or prevention of Extra Pyramidal Syndrome,dystonia, restless leg syndrome (RLS) or periodic limb movement in sleep(PLMS) in PCT/US03/40456, filed Dec. 17, 2003, and have been disclosedas being useful in the treatment of attention deficit hyperactivitydisorder (ADHD) in WO 02/055083.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the structural Formula I:

wherein:

-   -   R¹ represents aryl or heteroaryl; and    -   R² represents hydrogen; or    -   R¹ and R² together with the carbon atoms to which they are        bonded form a further heterocyclic ring of the formula:

-   -    or a carbocyclic ring system of the formula:

-   -   R³ represents aryl, cycloalkylalkyl, aralkyl or heteroarylalkyl;    -   Z represents alkyl, alkenyl, haloalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, aralkyl or CH₂CH₂R⁴;    -   R⁴ represents a heterocycle selected from the group consisting        of:

and

-   -   R⁵ represents alkyl, alkoxycarbonyl, alkylsulfonyl, aryl or        heteroaryl;        or a pharmaceutically acceptable salt, solvate, ester or prodrug        thereof.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof Formula I in a pharmaceutically acceptable carrier.

Yet another aspect of the invention is a method of treating centralnervous system diseases such as depression, cognitive diseases andneurodegenerative diseases such as Parkinson's disease, senile dementiaor psychoses of organic origin, and stroke, comprising administering atherapeutically acceptable amount therefor of at least one compound ofFormula I to a mammal in need of such treatment.

The invention also relates to a method of treating attention relateddisorders, such as attention deficit disorder (ADD) and attentiondeficit hyperactivity disorder (ADHD), comprising administering atherapeutically acceptable amount therefor of at least one compound ofFormula I to a mammal in need of such treatment.

The invention also relates to a method of treating or preventingExtra-Pyramidal Syndrome (e.g., dystonia, akathisia, pseudoparkinsonismand tardive dyskinesia), of treating primary (idiopathic) dystonia, andof treating or preventing dystonia in patients who exhibit dystonia as aresult of treatment with a tricyclic antidepressant, lithium or ananticonvulsant, or who have used cocaine, comprising administering atherapeutically acceptable amount therefor of at least one compound ofFormula I to a mammal in need of such treatment.

The invention further relates to a method of treating abnormal movementdisorders, such as restless leg syndrome (RLS) or periodic limb movementin sleep (PLMS), comprising administering to a patient in need thereof atherapeutically effective amount therefor of at least one compound ofFormula I.

In particular, the invention is drawn to the method of treatingParkinson's disease comprising administering a therapeuticallyacceptable amount therefor of at least one compound of Formula I to amammal in need of such treatment.

Still another aspect of the invention is a method of treatingParkinson's disease with a combination of a therapeutically acceptableamount therefor of at least one compound of Formula I and one or moreagents useful in the treatment of Parkinson's disease, for exampledopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase,type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); or acatechol-O-methyltransferase (COMT) inhibitor.

The invention further relates to a pharmaceutical composition comprisinga therapeutically acceptable amount of at least one compound of FormulaI and one or more agents known to be useful in the treatment ofParkinson's disease in a pharmaceutically acceptable carrier.

The invention also comprises a method of treating RLS or PLMS comprisingadministering to a patient in need thereof a therapeutically acceptableamount of a combination of at least one compound of Formula I withanother agent useful in treating RLS or PLMS, such aslevodopa/carbidopa, levodopa/benserazide, a dopamine agonist, abenzodiazepine, an opioid, an anticonvulsant or iron.

DETAILED DESCRIPTION OF THE INVENTION

In one preferred embodiment, the compound of Formula I orpharmaceutically acceptable salt, solvate, ester or prodrug thereof isone wherein R¹ represents aryl; and R² represents hydrogen.

In another preferred embodiment, the compound of Formula I orpharmaceutically acceptable salt, solvate, ester or prodrug thereof isone wherein R¹ and R² together with the carbon atoms to which they arebonded form a further heteroaromatic ring of the formula:

In another preferred embodiment, the compound of Formula I orpharmaceutically acceptable salt, solvate, ester or prodrug thereof isone wherein R¹ and R² together with the carbon atoms to which they arebonded form a carbocyclic ring system of the formula:

In an especially preferred embodiment, the compound of Formula I orpharmaceutically acceptable salt, solvate, ester or prodrug thereof isone wherein:

-   -   R¹ represents aryl; and    -   R² represents hydrogen; or    -   R¹ and R² together with the carbon atoms to which they are        bonded form a further heteroaromatic ring of the formula:

-   -    or a carbocyclic ring system of the formula:

-   -   R³ represents aralkyl; and    -   Z represents alkenyl or haloalkyl.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, 2-propynyl, 2-butynyl and 3-methyl-1-butynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and, wherein Y₁ and Y₂ canbe the same or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. “Ringsystem substituent” may also mean a single moiety which simultaneouslyreplaces two available hydrogens on two adjacent carbon atoms (one H oneach carbon) on a ring system. Examples of such moiety aremethylenedioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso include a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Examples of such moiety are 2-pyrrolidone:

and 3-pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl,dihydrothiopyranyl, and the like. “Heterocyclenyl” may also include asingle moiety (e.g., carbonyl) which simultaneously replaces twoavailable hydrogens on the same carbon atom on a ring system. An exampleof such moiety is 1,2-dihydro-pyrrol-3-one:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an'alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “pharmaceutical composition” means a composition, as definedabove, in a form and comprising active ingredients, vehicles, carriersand/or auxiliaries suitable for pharmaceutical use.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula Ior a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula I or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as,for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula I contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula I incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —CH(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —CH(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —CH(Y⁴)Y⁵ wherein Y⁴ is H or methyl andY⁵ is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, methyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino alcohol). All such tautomeric forms are contemplated herein aspart of the present invention.

The compounds of Formula I may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula I as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula I incorporatesa double bond or a fused ring, both the cis- and trans-forms, as well asmixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula I may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula I (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula I cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

In general, the compounds of this invention may be prepared from knownor readily prepared starting materials, following methods known to oneskilled in the art of organic synthesis. Methods useful for making the[1,2,4]triazolo[4,3-c]pyrimidin-3-one derivatives are set forth in theExamples below and generalized in Schemes 1-3. Alternative syntheticpathways and analogous structures will be apparent to those skilled inthe art of organic synthesis. All stereoisomers and tautomeric forms ofthe compounds are contemplated.

The preparation of compounds of structure E is illustrated in Scheme 1.Suzuki coupling of dichloride A with various boronic acids providespyrimidines B. Subsequent chloride displacement with hydrazine yieldspyrimidine C. Condensation of pyrimidine C with various aldehydes andreduction with sodium cyanoborohydride gives pyrimidine D. Treatment ofcompound D with phosgene provides compounds with the general structureE.

The preparation of compounds of structure M is illustrated in Scheme 2.The preparation of hydrazine J is known (US 2005/0239795A1).Condensation of hydrazine J with various aldehydes followed by reductionwith sodium cyanoborohydride provides compounds K. Treatment of compoundK with phosgene provides chlorides L. Chloride L may be reacted withamines R_(a)R_(b)NH in DMF at elevated temperature to provide compoundsM.

Scheme 3 illustrates a method for making compounds of formula V.Treatment of α-tetralone with NaH and Me₂CO₃ provides compound O.Reaction of compound O with NaOMe and thiourea in MeOH provides compoundP. Treatment of compound P with 10% ClCH₂CO₂H at elevated temperaturegives compound Q. Subsequent treatment of compound Q with POCl₃ in DMFgives dichloride R. Reaction of dichloride R with hydrazine hydrate,condensation with various aldehydes, and reduction with NaBH₃(CN)provides compounds T. Treatment of compound T with phosgene followed bychloride displacement with 2M NH₃ in isopropanol provides compounds V.

The starting materials and reagents depicted in Schemes 1-3 are eitheravailable from commercial suppliers such as Sigma-Aldrich (St. Louis,Mo.) and Acros Organics Co. (Fair Lawn, N.J.), or can be prepared usingmethods well-known to those of skill in the art of organic synthesis.

One skilled in the art will recognize that the synthesis of compounds ofFormula I may require protection of certain functional groups (i.e.,derivatization for the purpose of chemical compatibility with aparticular reaction condition). Suitable protecting groups for thevarious functional groups of the compounds of Formula I and methods fortheir installation and removal may be found in Greene et. al.,Protective Groups in Organic Synthesis, Wiley-Interscience, New York,(1999).

EXAMPLES

The following examples constitute illustrative examples of compounds ofthe present invention and are not to be construed as limiting the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

General Methods

Solvents, reagents, and intermediates that are commercially availablewere used as received. Reagents and intermediates that are notcommercially available were prepared in the manner described below.Microwave reactions were performed using the Biotage Initiatormicrowave. ¹H NMR spectra were obtained on a Gemini AS-400 (400 MHz) andare reported as ppm downfield from Me₄Si with number of protons,multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses were performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min—10% CH₃CN, 5 min—95% CH₃CN, 7 min—95% CH₃CN, 7.5min—10% CH₃CN, 9 min—stop. The observed parent ion is given.

The following solvents and reagents may be referred to by theirabbreviations:

Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; Ph=phenyl, and Ac=acetylμl=microlitersEtOAc=ethyl acetateAcOH or HOAc=acetic acidAtm=atmosphereBINAP=rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthylBoc or BOC=tert-butoxycarbonyl

BSA=N,O-(bistrimethylsilyl)acetamide

CH₂Cl₂=dichloromethaneDIPEA=diisoproylethylamineDMAP=4-dimethylaminopyridineDMF=dimethylformamideDMSO=dimethylsulfoxideEDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimideEDTA=ethylenediaminetetraacetic acidEtOH=ethanolg=gramsh=hourHOBt=1-hydroxybenzotriazoleLAH=lithium aluminum hydrideLCMS or LC/MS=liquid chromatography mass spectrometrymin=minutemg=milligramsmL=millilitersmmol=millimolesmCPBA=3-chloroperoxybenzoic acidMeOH=methanolMS=mass spectrometryNMR=nuclear magnetic resonance spectrometryRT or rt=room temperature (ambient, about 25° C.)TEA or Et₃N=triethylamineTFA=trifluoroacetic acidTHF=tetrahydrofuranTLC=thin layer chromatographyTMS=trimethylsilylTMSOTf=trimethylsilyl trifluoromethanesulfonateTBS=tert-butyldimethylsilylX-Phos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

In general, the compounds of this invention may be prepared from knownor readily prepared starting materials, following methods known to oneskilled in the art of organic synthesis. All stereoisomers andtautomeric forms of the compounds are contemplated.

Example 1 Preparation of Compound 1

Step A—Synthesis of Compound 1b

To Me₂CO₃ (9 mL) was added NaH (60% dispersion in oil, 2.52 g, 1.51mmol) and the solution was heated to 90° C. for 5 min. To the solutionα-tetralone (4.00 g, 27.4 mmol) in Me₂CO₃ (9 mL) was added and thesolution was stirred at 115° C. for 6 h. Allowed to cool, added MeOH(0.9 mL), added 3M HCl (93 mL), transferred to sep funnel, extractedwith ether, washed with sat. aq. NaHCO₃, washed with H₂O, washed withbrine, dried (MgSO₄), filtered, and concentrated. Crude product waspurified by flash column chromatography to yield compound 1b (4.5 g,80%).

Step B—Synthesis of Compound 1c

Sodium metal (0.62 g, 26.7 mmol) was added to MeOH (12 mL) and stirredfor 30 min. Compound 1b (2.2 g, 10.8 mmol) in MeOH (15 mL) was added andthiourea (0.90 g, 11.8 mmol) was added and the solution was heated to70° C. for 12 h. Allowed reaction to cool and concentrated under vacuum.To the solid was added H₂O (100 mL), acidified to pH=5 with AcOH,filtered solid, rinsed solid with sat. aq. NaHCO₃, rinsed with H₂O, anddried to give compound 1c (0.56 g, 22%).

Step C—Synthesis of Compound 1d

To the product of Step B (0.56 g, 2.4 mmol) was added 10% ClCH₂CO₂H (60mL) and the solution was heated to 105° C. for 12 h. Allowed to cool,filtered off solid, rinsed with 95% ethanol, rinsed with ether, anddried to give compound 1d (0.20 g, 38%).

Step D—Synthesis of Compound 1e

To the product of Step C (0.20 g, 0.93 mmol) was added POCl₃ (15 mL) and5 drops of DMF. The solution was heated to 110° C. for 46 h. Allowed tocool and concentrated under vacuum. Poured crude residue onto ice waterand stirred for 20 min. Solution was partitioned between CH₂Cl₂ and H₂O,washed organic layer with brine, dried (MgSO₄), filtered, andconcentrated to yield compound 1e.

Step E—Synthesis of Compound 1f

To compound 1e in EtOH (6 mL) was added hydrazine monohydrate (0.09 mL)and DMF (3 mL). The solution was stirred for 3 h. Filtered the reactionto provide compound 1f (0.24 g, 100%)

Step F—Synthesis of Compound 1g

To compound 1f (0.24 g, 0.90 mmol) was added benzaldehyde (0.104 mL, 1.4mmol), AcOH (0.08 mL), and CH₂Cl₂ (30 mL). The solution was stirred for30 min at room temperature and 45 min at 40° C. Allowed to cool, addedNaBH₃(CN) (0.18 g, 2.7 mmol) and the solution was heated to 40° C. for43 h. Solution was partitioned between CH₂Cl₂ and H₂O, washed withbrined, dried (MgSO₄), filtered and concentrated to give compound 1g(0.4 g, 100%).

Step G—Synthesis of Compound 1

To compound 1g (0.4 g, 0.90 mmol) was added CH₂Cl₂ (20 mL), DIPEA (0.52mL, 2.3 mmol), and phosgene (20% in toluene, 1.12 mL, 1.6 mmol). Thesolution was stirred for 30 min at 0° C. and 10 min at room temperature.Triturated solid with MeOH, filtered, and dried to yield compound 1h. Tocompound 1h was added 2M NH₃ in isopropanol (15 mL) in a sealed tube,stirred and heated to 110° C. for 20 h. Allowed to cool, concentratedunder vacuum, triturated with MeOH to give compound 1 as a white solid(0.12 g, 30%).

Example 2 Preparation of Compound 2

Step A—Synthesis of Compound 2b

To compound 2a (2.0 g, 12.2 mmol) was added CH₃CN (40 mL), K₂CO₃ (2Msolution, 6.1 mL, 12.2 mmol), Pd(PPh₃)₄ (0.35 g, 0.31 mmol), andPhB(OH)₂ (0.74 g, 6.1 mmol). The solution was stirred and heated to 90°C. for 4 h. Allowed to cool, transferred to sep. funnel, added CH₂Cl₂(50 mL), added H₂O (50 mL), mixed, separated, extracted aqueous layerwith CH₂Cl₂, combined organic layers, dried (MgSO₄), filtered, andconcentrated. Purified using preparative thin layer chromatography (100%CH₂Cl₂) to yield compound 2b (0.8 g, 64%).

Step B—Synthesis of Compound 2c

To compound 2b (0.8 g, 3.9 mmol) was added EtOH (40 mL) and hydrazinehydrate (0.38 mL, 7.78 mmol) and the solution was stirred for 24 h.Filtered solid, rinsed with MeOH, and dried to yield compound 2c (0.75g, 96%).

Step C—Synthesis of Compound 2d

Using Step F from Example 1, substituting compound 2c for compound 1f,compound 2d was prepared.

Step D—Synthesis of Compound 2

To compound 2d (0.2 g, 0.69 mmol) was added THF (15 mL), DIPEA (0.24 mL,1.37 mmol), and phosgene (20% solution in toluene, 0.73 mL, 1.37 mmol).The solution was stirred for 30 min. Transferred to sep. funnel, addedCH₂Cl₂ (50 mL), added H₂O (50 mL), mixed, separated, extracted aqueouslayer with CH₂Cl₂, combined organic layers, dried (MgSO₄), filtered, andconcentrated. Purified using thin layer chromatography (100% CH₂Cl₂) toyield compound 2 (0.022 g, 10%).

Example 3 Preparation of Compound 3

Step A—Synthesis of Compound 3a

To compound 2a (3.0 g, 18.3 mmol) was added THF (100 mL), DIPEA (15.9mL, 91.5 mmol), and benzylhydrazine hydrochloride (3.9 g, 20.1 mmol).The solution was stirred at 60° C. for 3 h. Allowed to cool, transferredto sep. funnel, added CH₂Cl₂ (100 mL), added H₂O (100 mL), mixed,separated, extracted aqueous layer with CH₂Cl₂, combined organic layers,dried (MgSO₄), filtered, and concentrated to yield compound 3a (4.4 g,96%).

Step B—Synthesis of Compound 3b

To compound 3a (2.5 g, 10.0 mmol) was added THF (100 mL), DIPEA (5.2 mL,30 mmol), and phosgene (20% solution in toluene, 8 mL, 15 mmol) and thesolution was stirred at 0° C. for 1 h. Allowed to cool, transferred tosep. funnel, added CH₂Cl₂ (100 mL), added H₂O (100 mL), mixed,separated, extracted aqueous layer with CH₂Cl₂, combined organic layers,dried (MgSO₄), filtered, and concentrated. Purified crude material byflash column chromatography using silica gel (1-5% MeOH/CH₂Cl₂) toprovide compound 3b as a white solid (1.2 g, 44%).

Step C—Synthesis of Compound 3

Using Step A from Example 2, substituting 4-methoxyphenylboronic acidfor phenylboronic acid and substituting compound 3b for compound 2a,compound 3 was prepared.

Example 4 Preparation of Compound 4

Compound 4 was synthesized using Step C described in Example 3,substituting 3-pyridylboronic acid for 4-methoxyphenylboronic acid.

Example 5 Preparation of Compound 7

Step A—Synthesis of Compound 7b

To compound 7a (preparation described in patent US 2005/0239795A1, 2.0g, 8.8 mmol) was added TFA (30 mL) and benzaldehyde (0.99 mL, 9.7 mmol)and the solution was stirred for 30 min. To the solution was addedEt₃SiH (7.0 mL, 44 mmol) and the solution was stirred for 6 h. Added H₂O(50 mL), CH₂Cl₂ (50 mL), and added conc. NH₄OH until pH 10. Transferredto sep. funnel, added 300 mL EtOAc, H₂O (100 mL), mixed, separated,extracted aqueous layer with EtOAc, combined organic layers, dried(MgSO₄), filtered, and concentrated to yield compound 7b (2.0 g, 72%).

Step B—Synthesis of Compound 7

Using Step B from Example 3, substituting compound 7b for compound 3a,compound 7 was prepared.

Example 6 Preparation of Compound 8

Compound 8 was synthesized using Steps A and B from Example 5,substituting 3-chlorobenzaldehyde for benzaldehyde.

Example 7 Preparation of Compound 28

Compound 28 was synthesized using Steps A and B from Example 5,substituting cyclopropanecarbaldehyde for benzaldehyde.

Example 8 Preparation of Compound 6

Step A—Synthesis of Compound 6

To compound 8 (150 mg, 0.40 mmol) was added DMF (1.5 mL), and DBU (0.12mL, 0.80 mmol) and the solution was stirred and heated to 100° C. for 14h. Allowed to cool, concentrated under vacuum, and purified bypreparative TLC using (1% MeOH/CH₂Cl₂) to yield compound 6 (33 mg, 24%).

Example 9 Preparation of Compound 5

Compound 5 was synthesized using Step A from Example 8, substitutingcompound 7 for compound 8.

Example 10 Preparation of Compound 23

Compound 23 was synthesized using Step A from Example 8, substitutingcompound 28 for compound 8.

Example 11 Preparation of Compound 29

Using Steps A and B described in Example 3, substituting compound 29a(prepared using methods to prepare compound 7a, patent US 2005/0239795A)for compound 2a, and substituting phenyl hydrazine for benzylhydrazinehydrochloride, compound 29 was prepared.

Example 12 Preparation of Compound 27

Step A—Synthesis of Compound 27

To compound 8 (100 mg, 0.26 mmol) was added DMF (3 mL), KI (44 mg, 0.26mmol), and dimethylamine (40% in H₂O, 0.045 mL, 0.35 mmol). The solutionwas stirred at 140° C. for 14 h. Allowed to cool, concentrated undervacuum, and purified by preparative TLC using (5% CH₃OH/CH₂Cl₂) to yieldcompound 27 (11 mg, 11%).

Example 13 Preparation of Compound 9

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting aryl-piperazine 9a (prepared in patent US 2005/0239795A)for dimethylamine, compound 9 was prepared.

Example 14 Preparation of Compound 10

Using Step A from Example 12, substituting 4-(piperidin-4-yl)-morpholinefor dimethylamine, compound 10 was prepared.

Example 15 Preparation of Compound 11

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting 1,4-dioxa-8-azaspiro[4.5]decane for dimethylamine, compound11 was prepared.

Example 16 Preparation of Compound 12

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting 1-(methylsulfonyl)piperazine for dimethylamine, compound 12was prepared.

Example 17 Preparation of Compound 13

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting morpholine for dimethylamine, compound 13 was prepared.

Example 18 Preparation of Compound 14

Using Step A from Example 12, substituting 1-(methylsulfonyl)piperazinefor dimethylamine, compound 14 was prepared.

Example 19 Preparation of Compound 15

Using Step A from Example 12, substituting1,4-dioxa-8-azaspiro[4.5]decane for dimethylamine, compound 15 wasprepared.

Example 20 Preparation of Compound 16

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting 2-(piperazin-1-yl)pyrazine for dimethylamine, compound 16was prepared.

Example 21 Preparation of Compound 17

Using Step A from Example 12, substituting 2-(piperazin-1-yl)pyrazinefor dimethylamine, compound 17 was prepared.

Example 22 Preparation of Compound 18

Using Step A from Example 12, substituting morpholine for dimethylamine,compound 18 was prepared.

Example 23 Preparation of Compound 19

Using Step A from Example 12, substituting1-(4-(2-methoxyethoxy)phenyl)piperazine for dimethylamine, compound 19was prepared.

Example 24 Preparation of Compound 20

Using Step A from Example 12, substituting compound 9a fordimethylamine, compound 20 was prepared.

Example 25 Preparation of Compound 21

Using Step A from Example 12, substituting 1-p-tolylpiperazine fordimethylamine, compound 21 was prepared.

Example 26 Preparation of Compound 22

Using Step A from Example 12, substituting1-(2,4-difluorophenyl)piperazine for dimethylamine, compound 22 wasprepared.

Example 27 Preparation of Compound 24

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting 4-(piperidin-4-yl)-morpholine for dimethylamine, compound24 was prepared.

Example 28 Preparation of Compound 25

Using Step A from Example 12, substituting compound 28 for compound 8and substituting compound 9a for dimethylamine, compound 25 wasprepared.

Example 29 Preparation of Compound 26

Using Step A from Example 12, substituting 1-methylpiperazine fordimethylamine, compound 26 was prepared.

Example 30 Preparation of Compound 30

Using Step A from Example 12, substituting compound 28 for compound 8and substituting morpholine for dimethylamine, compound 30 was prepared.

Example 31 Preparation of Compound 31

Step A—Synthesis of Compound 31b

To compound 31a (5.0 g, 32 mmol) was added CH₂Cl₂ (40 mL) and Fe powder(80 mg, 1.44 mmol) and to this solution Br₂ (1.8 mL, 35 mmol) in CH₂Cl₂(20 mL) was added slowly and the solution was stirred for 4 h. Pouredsolution into H₂O (100 mL), transferred to sep. funnel, separatedlayers, washed organic layer with 10% NaOH_(aq), washed with H₂O, dried(MgSO₄), filtered, and concentrated to yield compound 31b (7.9 g, 100%).

Step B—Synthesis of Compound 31c

To compound 31b (2.0 g, 8.5 mmol) was added piperazine (4.4 g, 51 mmol),BINAP (318 mg, 0.51 mmol), Pd₂ dba₃ (98 mg, 0.17 mmol), NaOtBu (1.14 g,11.9 mmol), and toluene (15 mL). The solution was stirred and heated to110° C. for 24 h. Allowed to cool, extracted solution with 1N HCl,basified with 1N NaOH to pH 12, extracted with CH₂Cl₂, dried (MgSO₄),filtered, and concentrated to yield compound 31c (1.9 g, 90%).

Step C—Synthesis of Compound 31

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting compound 31c for dimethylamine, compound 31 was prepared.

Example 32 Preparation of Compound 32

Using Step A from Example 12, substituting 1-Boc-piperazine fordimethylamine, compound 32 was prepared.

Example 33 Preparation of Compound 33

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting compound 33a (patent US 2005/0239795A) for dimethylamine,compound 33 was prepared.

Example 34 Preparation of Compound 34

Using Step A from Example 12, substituting compound 5 for compound 8 andsubstituting compound 34a (patent US 2005/0239795A) for dimethylamine,compound 34 was prepared.

Example 35 LC/MS Data For Selected Compounds

LC/MS data for selected [1,2,4]triazolo[4,3-c]pyrimidin-3-onederivatives is provided below in Table 1, wherein the compound numberscorrespond to the compound numbering set forth in the abovespecification.

TABLE 1 LC/MS Data For Selected [1,2,4]triazolo[4,3-c]pyrimidin-3-oneDerivatives LCMS LCMS Compound Compound Calculated Observed No. Name M +1 M + 1 1 11-AMINO-4,5-DIHYDRO-2- 344.382 344.2(PHENYLMETHYL)BENZO[h][1,2,4]TRIAZOLO[4,3- c]QUINAZOLIN-1(2H)-ONE 25-AMINO-7-PHENYL-2-(PHENYLMETHYL)-1,2,4- 318.1 318.2TRIAZOLO[4,3-c]PYRIMIDIN-3(2H)-ONE 3 5-AMINO-7-(4-METHOXYPHENYL)-2-348.1 348.2 (PHENYLMETHYL)-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN- 3(2H)-ONE 45-AMINO-2-(PHENYLMETHYL)-7-(3-PYRIDINYL)- 319.1 319.21,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3(2H)-ONE 55-AMINO-7-ETHENYL-2,7-DIHYDRO-2- 308.1 308.2(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4- TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE6 5-AMINO-2-[(3-CHLOROPHENYL)METHYL]-7- 341.1 342.2ETHENYL-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 75-AMINO-7-(2-CHLOROETHYL)-2,7-DIHYDRO-2- 344.1 344.2(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4- TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE8 5-AMINO-7-(2-CHLOROETHYL)-2-[(3- 378.1 378.2CHLOROPHENYL)METHYL]-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN- 3-ONE 95-AMINO-7-[2-[4-[2-FLUORO-5-(5-METHYL-1,2,4- 570.2 570.3OXADIAZOL-3-YL)PHENYL]-1-PIPERAZINYL]ETHYL]-2,7-DIHYDRO-2-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN- 3-ONE 105-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,7- 512.2 512.3DIHYDRO-7-[2-[4-(4-MORPHOLINYL)-1-PIPERIDINYL]ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 115-AMINO-7-[2-(1,4-DIOXA-8-AZASPIRO[4.5]DEC-8- 451.2 451.2YL)ETHYL]-2,7-DIHYDRO-2-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 121-[2-[5-AMINO-2,3-DIHYDRO-3-OXO-2- 472.1 472.3(PHENYLMETHYL)-7H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-7-YL]ETHYL]-4- [METHYLSULFONYL]PIPERAZINE 135-AMINO-2,7-DIHYDRO-7-[2-(4-MORPHOLINYL)ETHYL]- 395.2 395.22-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 141-[2-[5-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,3- 506.1 506.3DIHYDRO-3-OXO-7H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-7-YL]ETHYL]-4- (METHYLSULFONYL)PIPERAZINE 155-AMINO-2-[(3-CHLOROPHENYL)METHYL]-7-[2-(1,4- 485.2 485.3DIOXA-8-AZASPIRO[4.5]DEC-8-YL)ETHYL]-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3- c]PYRIMIDIN-3-ONE 165-AMINO-2,7-DIHYDRO-2-(PHENYLMETHYL)-7-[2-(4- 472.2 472.3PYRAZINYL-1-PIPERAZINYL)ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 175-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,7- 506.2 506.3DIHYDRO-7-[2-(4-PYRAZINYL-1-PIPERAZINYL)ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3- c]PYRIMIDIN-3-ONE 185-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,7- 429.2 429.2DIHYDRO-7-[2-(4-MORPHOLINYL)ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 195-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,7- 578.2 578.2DIHYDRO-7-[2-[4-[4-(2-METHOXYETHOXY)PHENYL]-1-PIPERAZINYL]ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 205-AMINO-2-[(3-CHLOROPHENYL)METHYL]-7-[2-[4-[2- 604.2 604.3FLUORO-5-(5-METHYL-1,2,4-OXADIAZOL-3-YL)PHENYL]-1-PIPERAZINYL]ETHYL]-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3- c]PYRIMIDIN-3-ONE 215-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,7- 518.2 518.3DIHYDRO-7-[2-[4-(4-METHYLPHENYL)-1-PIPERAZINYL]ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 225-AMINO-2-[(3-CHLOROPHENYL)METHYL]-7-[2-[4-(2,4- 540.2 540.3DIFLUOROPHENYL)-1-PIPERAZINYL]ETHYL]-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3- c]PYRIMIDIN-3-ONE 235-AMINO-2-(CYCLOPROPYLMETHYL)-7-ETHENYL-2,7- 272.1 272.1DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3- c]PYRIMIDIN-3-ONE 245-AMINO-2,7-DIHYDRO-7-[2-[4-(4-MORPHOLINYL)-1- 478.3 478.3PIPERIDINYL]ETHYL]-2-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 255-AMINO-2-(CYCLOPROPYLMETHYL)-7-[2-[4-[2- 534.2 534.3FLUORO-5-(5-METHYL-1,2,4-OXADIAZOL-3-YL)PHENYL]-1-PIPERAZINYL]ETHYL]-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3- c]PYRIMIDIN-3-ONE 265-AMINO-2-[(3-CHLOROPHENYL)METHYL]-2,7- 442.2 442.2DIHYDRO-7-[2-(4-METHYL-1-PIPERAZINYL)ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 275-AMINO-2-[(3-CHLOROPHENYL)METHYL]-7-[2- 387.1 387.2(DIMETHYLAMINO)ETHYL]-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 285-AMINO-7-(2-CHLOROETHYL)-2- 308.1 308.2(CYCLOPROPYLMETHYL)-2,7-DIHYDRO-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3- ONE 295-AMINO-2,7-DIHYDRO-2-PHENYL-7-(2- 372.2 372.2PHENYLETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4- TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 305-AMINO-2-(CYCLOPROPYLMETHYL)-2,7-DIHYDRO-7- 359.2 359.2[2-(4-MORPHOLINYL)ETHYL]-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 315-AMINO-7-[2-[4-(2-FLUORO-4,5-DIMETHOXYPHENYL)- 548.3 548.31-PIPERAZINYL]ETHYL]-2,7-DIHYDRO-2-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4- TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE32 1,1-DIMETHYLETHYL 4-[2-[5-AMINO-2-[(3- 528.2 528.3CHLOROPHENYL)METHYL]-2,3-DIHYDRO-3-OXO-7H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-7-YL]ETHYL]-1-PIPERAZINECARBOXYLATE 335-AMINO-7-[2-[4-[2-FLUORO-5-(5-METHYL-1,3,4- 570.2 570.3OXADIAZOL-2-YL)PHENYL]-1-PIPERAZINYL]ETHYL]-2,7-DIHYDRO-2-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4-TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE 345-AMINO-2,7-DIHYDRO-7-[2-[4-[3-(5-METHYL-1,3,4- 552.3 552.3OXADIAZOL-2-YL)PHENYL]-1-PIPERAZINYL]ETHYL]-2-(PHENYLMETHYL)-3H-PYRAZOLO[4,3-e]-1,2,4- TRIAZOLO[4,3-c]PYRIMIDIN-3-ONE

Because of their adenosine A_(2a) receptor antagonist activity,compounds of the present invention are useful in the treatment ofdepression, cognitive function diseases and neurodegenerative diseasessuch as Parkinson's disease, senile dementia as in Alzheimer's disease,psychoses of organic origin, attention deficit disorders, EPS, dystonia,RLS and PLMS. In particular, the compounds of the present invention canimprove motor-impairment due to neurodegenerative diseases such asParkinson's disease.

The other agents known to be useful in the treatment of Parkinson'sdisease that can be administered in combination with the compounds ofFormula I include: L-DOPA; dopaminergic agonists such as quinpirole,ropinirole, pramipexole, pergolide and bromocriptine; MAO-B inhibitorssuch as deprenyl and selegiline; DOPA decarboxylase inhibitors such ascarbidopa and benserazide; and COMT inhibitors such as tolcapone andentacapone.

In this specification, the term “at least one compound of Formula I” (ora pharmaceutically acceptable salt, solvate, ester or prodrug thereof)means that one to three different compounds of Formula I (orpharmaceutically acceptable salt, solvate, ester or prodrug thereof) maybe used in a pharmaceutical composition or method of treatment.Preferably one compound of Formula I or pharmaceutically acceptablesalt, solvate, ester or prodrug thereof is used. Similarly, “one or moreagents useful in the treatment of Parkinson's disease” means that one tothree different agents, preferably one agent, may be used in apharmaceutical composition or method of treatment. Preferably, one agentis used in combination with one compound of Formula I orpharmaceutically acceptable salt, solvate, ester or prodrug thereof.

The pharmacological activity of the compounds of the invention wasdetermined by the following in vitro assays to measure A_(2a) receptoractivity.

Human Adenosine A_(2a) and A₁ Receptor Competition Binding AssayProtocol Membrane Sources:

A_(2a): Human A_(2a) Adenosine Receptor membranes, Catalog #RB-HA2a,Receptor Biology, Inc., Beltsville, Md. Dilute to 17 μg/100 μl inmembrane dilution buffer (see below).

Assay Buffers:

Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline(Gibco/BRL)+10 mM MgCl₂.

Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline(Gibco/BRL)+10 mM MgCl₂ supplemented with 1.6 mg/ml methyl cellulose and16% DMSO. Prepared fresh daily.

Ligands:

A_(2a): [3H]-SCH 58261, custom synthesis, AmershamPharmacia Biotech,Piscataway, N.J. Stock is prepared at 1 nM in membrane dilution buffer.Final assay concentration is 0.5 nM.

A₁: [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J. Stock isprepared at 2 nM in membrane dilution buffer. Final assay concentrationis 1 nM.

Non-Specific Binding:

A_(2a): To determine non-specific binding, add 100 nM CGS15923 (RBI,Natick, Mass.). Working stock is prepared at 400 nM in compound dilutionbuffer.

A₁: To determine non-specific binding, add 100 μM NECA (RBI, Natick,Mass.). Working stock is prepared at 400 μM in compound dilution buffer.

Compound Dilution:

Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute incompound dilution buffer. Test at 10 concentrations ranging from 3 μM to30 pM. Prepare working solutions at 4× final concentration in compounddilution buffer.

Assay Procedure:

Perform assays in deep well 96 well plates. Total assay volume is 200μl. Add 50 μl compound dilution buffer (total ligand binding) or 50 μlCGS 15923 working solution (A_(2a) non-specific binding) or 50 μl NECAworking solution (A₁ non-specific binding) or 50 μl of drug workingsolution. Add 50 μl ligand stock ([3H]-SCH 58261 for A_(2a), [3H]-DPCPXfor A₁). Add 100 μl of diluted membranes containing the appropriatereceptor. Mix. Incubate at room temperature for 90 minutes. Harvestusing a Brandel cell harvester onto Packard GF/B filter plates. Add 45μl Microscint 20 (Packard), and count using the Packard TopCountMicroscintillation Counter. Determine IC₅₀ values by fitting thedisplacement curves using an iterative curve fitting program (Excel).Determine K_(i) values using the Cheng-Prusoff equation.

Using the above test procedures, the following results were obtained forpreferred and/or representative compounds of the invention.

Results of the binding assay on compounds of the invention showed A_(2a)K_(i) values of 0.3 to 791 nM, with preferred compounds showing K_(i)values between 0.3 and 5.0 nM. Selectivity is determined by dividingK_(i) for A₁ receptor by K_(i) for A₂ receptor. Preferred compounds ofthe invention have a selectivity ranging from about 100 to about 1500.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound of formula I in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg, morepreferably from about 1 mg to 300 mg, according to the particularapplication. The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the'judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen for compounds of formula I is oral administration of from10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to fourdivided doses to provide relief from central nervous system diseasessuch as Parkinson's disease or the other disease or conditions listedabove.

The doses and dosage regimen of the dopaminergic agents will bedetermined by the attending clinician in view of the approved doses anddosage regimen in the package insert, taking into consideration the age,sex and condition of the patient and the severity of the disease. It isexpected that when the combination of a compound of Formula I and adopaminergic agent is administered, lower doses of the components willbe effective compared to the doses of the components administered asmonotherapy.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound represented by the structural Formula I:

wherein: R¹ represents aryl or heteroaryl; and R² represents hydrogen;or R¹ and R² together with the carbon atoms to which they are bondedform a further heterocyclic ring of the formula:

 or a carbocyclic ring system of the formula:

R³ represents aryl, cycloalkylalkyl, aralkyl or heteroarylalkyl; Zrepresents alkyl, alkenyl, haloalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aralkyl or CH₂CH₂R⁴; R⁴ represents a member selectedfrom the group consisting of:

and R⁵ represents alkyl, alkoxycarbonyl, alkylsulfonyl, aryl orheteroaryl; or a pharmaceutically acceptable salt, solvate, ester orprodrug of said compound of Formula I.
 2. The compound of claim 1, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof,wherein R¹ represents aryl; and R² represents hydrogen.
 3. The compoundof claim 1, or a pharmaceutically acceptable salt, solvate, ester orprodrug thereof, wherein R¹ and R² together with the carbon atoms towhich they are bonded form a further heterocyclic ring of the formula:


4. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof, wherein R¹ and R² together with thecarbon atoms to which they are bonded form a carbocyclic ring system ofthe formula:


5. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof, wherein: R¹ represents aryl; and R²represents hydrogen; or R¹ and R² together with the carbon atoms towhich they are bonded form a further heterocyclic ring of the formula:

 or a carbocyclic ring system of the formula:

R³ represents aralkyl; and Z represents alkenyl or haloalkyl.
 6. Acompound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.
 7. A pharmaceutical composition comprising at least onecompound of claim 1, or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof and at least one pharmaceutically acceptablecarrier, adjuvant or vehicle.
 8. A pharmaceutical composition comprisingat least one compound of claim 6, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof and at least one pharmaceuticallyacceptable carrier, adjuvant or vehicle.
 9. The pharmaceuticalcomposition of claim 7, further comprising one or more additionaltherapeutic agents.
 10. The pharmaceutical composition of claim 8,further comprising one or more additional therapeutic agents.
 11. Thepharmaceutical composition of claim 9, wherein the one or moreadditional therapeutic agents are one or more therapeutic agents usefulfor the treatment of Parkinson's Disease.
 12. The pharmaceuticalcomposition of claim 10, wherein the one or more additional therapeuticagents are one or more therapeutic agents useful for the treatment ofParkinson's disease.
 13. The pharmaceutical composition of claim 11,wherein the one or more therapeutic agents useful for the treatment ofParkinson's disease are one or more therapeutic agents selected from thegroup consisting of L-DOPA, dopaminergic agonists, MAO-B inhibitors,DOPA decarboxylase inhibitors and COMT inhibitors.
 14. Thepharmaceutical composition of claim 12, wherein the one or moretherapeutic agents useful for the treatment of Parkinson's disease areone or more therapeutic agents selected from the group consisting ofL-DOPA, dopaminergic agonists, MAO-B inhibitors, DOPA decarboxylaseinhibitors and COMT inhibitors.
 15. A method of treating a disease ofthe central nervous system or stroke, comprising administering aneffective amount therefor of a compound of claim 1 or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof to a mammal in needof such treatment.
 16. The method of claim 15, wherein the disease ofthe central nervous system is depression, a cognitive disease or aneurodegenerative disease.
 17. The method of claim 15, wherein thedisease of the central nervous system is Parkinson's disease, seniledementia, a psychosis of organic origin, attention deficit disorder,Extra Pyramidal Syndrome, dystonia, restless leg syndrome or periodiclimb movement in sleep.
 18. A method of treating Parkinson's diseasecomprising administering an effective amount therefor of apharmaceutical composition according to claim 7 to a mammal in needthereof.
 19. The method of claim 18, wherein the pharmaceuticalcomposition comprises a therapeutically effective amount of a compoundselected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.
 20. The method of claim 18, wherein the pharmaceuticalcomposition additionally comprises one or more additional therapeuticagents are one or more therapeutic agents useful for the treatment ofParkinson's disease.
 21. The method of claim 20, wherein the one or moretherapeutic agents useful for the treatment of Parkinson's disease areone or more therapeutic agents selected from the group consisting ofL-DOPA, dopaminergic agonists, MAO-B inhibitors, DOPA decarboxylaseinhibitors and COMT inhibitors.